Methods of making and using novel griseofulvin compositions

Abstract

The present invention is directed to nanoparticulate compositions comprising griseofulvin. The griseofulvin particles of the composition preferably have an effective average particle size of less than about 2 microns.

1 .- 41 . (canceled)  
     
     
         42 . A method of making a griseofulvin composition comprising contacting particles of griseofulvin or a salt thereof with at least one surface stabilizer for a time and under conditions sufficient to provide a griseofulvin composition having an effective average particle size of less than about 2000 nm, wherein the surface stabilizer is not a polyalkylene block copolymer which gels at physiological temperature, and which contains one or more polyoxyethylene blocks and one or more polyoxy (higher alkylene) blocks, wherein at least some of the blocks are linked together by an oxymethylene group.  
     
     
         43 . The method of  claim 42 , wherein said contacting comprises grinding, wet grinding, homogenizing, precipitation, or a combination thereof.  
     
     
         44 .- 46 . (canceled)  
     
     
         47 . The method of  claim 42 , wherein the griseofulvin or a salt thereof is selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, and mixtures thereof.  
     
     
         48 . The method of  claim 42 , wherein the effective average particle size of the griseofulvin particles is selected from the group consisting of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1000 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm.  
     
     
         49 . The method of  claim 42 , wherein the composition is formulated: 
 (a) for administration selected from the group consisting of oral, pulmonary, rectal, opthalmic, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, local, buccal, nasal, and topical administrations    (b) into dosage form selected from the group consisting of liquid dispersions, oral suspensions, gels, aerosols, ointments, creams, tablets, and capsules;    (c) into a dosage form selected from the group consisting of controlled release formulations, fast melt formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations; or    (d) a combination thereof.    
     
     
         50 . The method of  claim 42 , wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or a combination thereof.  
     
     
         51 . The method of  claim 42 , wherein: 
 (a) griseofulvin or a salt thereof is present in an amount selected from the group consisting of from about 99.5% to about 0.001%, from about 95% to about 0.1%, and from about 90% to about 0.5%, by weight, based on the total combined dry weight of the griseofulvin or a salt thereof and at least one surface stabilizer, not including other excipients;    (b) at least one surface stabilizer is present in an amount selected from the group consisting of from about 0.5% to about 99.999%, from about 5.0% to about 99.9%, and from about 10% to about 99.5% by weight, based on the total combined dry weight of the griseofulvin or a salt thereof and at least one surface stabilizer, not including other excipients; or    (c) a combination thereof.    
     
     
         52 . (canceled)  
     
     
         53 . The method of  claim 42 , utilizing at least two surface stabilizers.  
     
     
         54 . The method of  claim 42 , wherein: 
 a the surface stabilizer is selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, and an ionic surface stabilizers;    (b) at least one surface stabilizer is selected from the group consisting of cetyl pyridinium chloride, gelatin, casein, phosphatides, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, Polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl celluloses, hypromellose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, poloxamers; poloxamines, a charged phospholipid, dioctylsulfosuccinate, dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkyl aryl polyether sulfonates, mixtures of sucrose stearate and sucrose distearate, p-isononylphenoxypoly-(glycidol), decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside; n-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexyl β-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside; octyl β-D-thioglucopyranoside; lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, and random copolymers of vinyl acetate and vinyl pyrrolidone;    (c) at least one cationic surface stabilizer is selected from the group consisting of cationic lipids, polymethylmethacrylate trimethylammonium bromide, sulfonium compounds, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyltrimethyl ammonium bromide, phosphonium compounds, quarternary ammonium compounds, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride, coconut trimethyl ammonium bromide, coconut methyl dihydroxyethyl ammonium chloride, coconut methyl dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride bromide, C 12-15 dimethyl hydroxyethyl ammonium chloride, C 12-15 dimethyl hydroxyethyl ammonium chloride bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl(ethenoxy) 4  ammonium chloride, lauryl dimethyl(ethenoxy) 4  ammonium bromide, N-alkyl(C 12-18 )dimethylbenzyl ammonium chloride, N-alkyl(C 14-18 )dimethyl-benzyl ammonium chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C 12-14 )dimethyl 1-napthylmethyl ammonium chloride, trimethylammonium halide, alkyl-trimethylammonium salts, dialkyl-dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkyamidoalkyldialkylammonium salt, an ethoxylated trialkyl ammonium salt, dialkylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium, chloride monohydrate, N-alkyl(C 12-14 ) dimethyl 1-naphthylmethyl ammonium chloride, dodecyldimethylbenzyl ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C 12  trimethyl ammonium bromides, C 15  trimethyl ammonium bromides, C 17  trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chlorides, alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride, POLYQUAT 10™, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts of quaternized polyoxyethylalkylamines, MIRAPOL™, ALKAQUAT™, alkyl pyridinium salts; amines, amine salts, amine oxides, imide azolinium salts, protonated quaternary acrylamides, methylated quaternary polymers, and cationic guar;    (d) the composition comprises as a surface stabilizer Tween® 80, Tetronic® T908, dioctylsulfosuccinate, polyvinyl acetate, Pluronic® F127, or a mixture thereof; or    (d) any combination thereof.    
     
     
         55 .- 57 . (canceled)  
     
     
         58 . The method of  claim 54 , wherein the composition is bioadhesive.  
     
     
         59 . (canceled)  
     
     
         60 . A method of treating a subject in need comprising administering to the subject an effective amount of a composition comprising: 
 (a) particles of a griseofulvin or a salt thereof, wherein the griseofulvin particles have an effective average particle size of less than about 2000 nm; and    (b) at least one surface stabilizer, wherein the surface stabilizer is not a polyalkylene block copolymer which gels at physiological temperature, and which contains one or more polyoxyethylene blocks and one or more polyoxy (higher alkylene) blocks, wherein at least some of the blocks are linked together by an oxymethylene group.    
     
     
         61 . The method of  claim 60 , wherein the griseofulvin or a salt thereof is selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, and mixtures thereof.  
     
     
         62 . The method of  claim 60 , wherein the effective average particle size of the griseofulvin particles is selected from the group consisting of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm.  
     
     
         63 . The method of  claim 60 , wherein the composition is formulated: 
 (a) for administration selected from the group consisting of oral, pulmonary, rectal, opthalmic, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, local, buccal, nasal, and topical administrations;    (b) into a dosage form selected from the group consisting of liquid dispersions, oral suspensions, gels, aerosols, ointments, creams, tablets, and capsules;    (c) into a dosage form selected from the group consisting of controlled release formulations, fast melt formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations; or    (d) a combination thereof.    
     
     
         64 . (canceled)  
     
     
         65 . The method of  claim 60 , wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or a combination thereof.  
     
     
         66 . The method of  claim 60 , wherein: 
 (a) griseofulvin or a salt thereof is present in an amount selected from the group consisting of from about 99.5% to about 0.001%, from about 95% to about 0.1%, and from about 90% to about 0.5%, by weight, based on the total combined dry weight of the griseofulvin or a salt thereof and at least one surface stabilizer, not including other excipients;    (b) at least one surface stabilizer is present in an amount selected from the group consisting of from about 0.5% to about 99.999% by weight, from about 5.0% to about 99.9% by weight, and from about 10% to about 99.5% by weight, based on the total combined dry weight of the griseofulvin or a salt thereof and at least one surface stabilizer, not including other excipients; or    (c) a combination thereof.    
     
     
         67 . (canceled)  
     
     
         68 . The method of  claim 60 , utilizing at least two surface stabilizers.  
     
     
         69 . The method of  claim 60 , wherein: 
 (a) the surface stabilizer is selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, and an ionic surface stabilizer;    (b) at least one surface stabilizer is selected from the group consisting of cetyl pyridinium chloride, gelatin, casein, phosphatides, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl celluloses, hypromellose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, poloxamers; poloxamines, a charged phospholipid, dioctylsulfosuccinate, dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkyl aryl polyether sulfonates, mixtures of sucrose stearate and sucrose distearate, p-isononylphenoxypoly-(glycidol), decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside; n-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexyl β-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside; octyl P-D-thioglucopyranoside; lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, and random copolymers of vinyl acetate and vinyl pyrrolidone;    (c) at least one cationic surface stabilizer is selected from the group consisting of a benzalkonium chloride, polymethylmethacrylate trimethylammonium bromide, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyltrimethyl ammonium bromide, cationic lipids, sulfonium compounds, phosphonium compounds, quarternary ammonium compounds, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride, coconut trimethyl ammonium bromide, coconut methyl dihydroxyethyl ammonium chloride, coconut methyl dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride bromide, C 12-15 dimethyl hydroxyethyl ammonium chloride, C 12-15 dimethyl hydroxyethyl ammonium chloride bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl(ethenoxy) 4  ammonium chloride, lauryl dimethyl(ethenoxy) 4  ammonium bromide, N-alkyl(C 12-18 )dimethylbenzyl ammonium chloride, N-alkyl(C 14-18 )dimethyl-benzyl ammonium chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C 12-14 )dimethyl 1-napthylmethyl ammonium chloride, trimethylammonium halide, alkyl-trimethylammonium salts, dialkyl-dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkyamidoalkyldialkylammonium salt, an ethoxylated trialkyl ammonium salt, dialkylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium, chloride monohydrate, N-alkyl(C 12-14 )dimethyl 1-naphthylmethyl ammonium chloride, dodecyldimethylbenzyl ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C 12  trimethyl ammonium bromides, C 15  trimethyl ammonium bromides, C 17  trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chlorides, alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride, POLYQUAT 10™, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts of quaternized polyoxyethylalkylamines, MIRAPOL™, ALKAQUAT™, alkyl pyridinium salts; amines, amine salts, amine oxides, imide azolinium salts, protonated quaternary acrylamides, methylated quaternary polymers, and cationic guar;    (d) the composition comprises as a surface stabilizer Tween® 80, Tetronic® T908, dioctylsulfosuccinate, polyvinyl acetate, Pluronic® F127, or a mixture thereof; or    (e) any combination thereof.    
     
     
         70 .- 72 . (canceled)  
     
     
         73 . The method of  claim 69 , wherein the composition is bioadhesive.  
     
     
         74 . (canceled)  
     
     
         75 . The method of  claim 60 , additionally comprising administering one or more non-griseofulvin active agents.  
     
     
         76 . The method of  claim 75 , wherein: 
 (a) said additional one or more non-griseofulvin active agents are selected from the group consisting of nutraceuticals, amino acids, proteins, peptides, nucleotides, anti-obesity drugs, central nervous system stimulants, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics, sedatives, astringents, alpha-adrenergic receptor blocking agents, beta-adrenoceptor blocking agents, blood products, blood substitutes, cardiac inotropic agents, contrast media, corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics, haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin, parathyroid biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones, anti-allergic agents, stimulants, anoretics, sympathomimetics, thyroid agents, vasodilators, and xanthines;    (b) at least one additional non-griseofulvin active agent is an anti-fungal agent;    (c) at least one additional non-griseofulvin active agent is vitamin E; or    (d) any combination thereof.    
     
     
         77 .- 78 . (canceled)  
     
     
         79 . The method of  claim 60 , wherein: 
 (a) the T max  of the griseofulvin, when assayed in the plasma of a mammalian subject following administration, is less than the T max  for a non-nanoparticulate griseofulvin formulation, administered at the same dosage;    (b) the C max  of the griseofulvin, when assayed in the plasma of a mammalian subject following administration, is greater than the C max  for a non-nanoparticulate griseofulvin formulation, administered at the same dosage;    (c) the AUC of the griseofulvin, when assayed in the plasma of a mammalian subject following administration, is greater than the AUC for a non-nanoparticulate griseofulvin formulation, administered at the same dosage; or    (d) a combination thereof.    
     
     
         80 . The method of  claim 79 , wherein: 
 (a) the T max  is selected from the group consisting of not greater than about 90%, not greater than about 80%, not greater than about 70%, not greater than about 60%, not greater than about 50%, not greater than about 30%, not greater than about 25%, not greater than about 20%, not greater than about 15%, not greater than about 10%, and not greater than about 5% of the T max  exhibited by a non-nanoparticulate griseofulvin formulation, administered at the same dosage;    (b) the C max  is selected from the group consisting of at least about 50%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%, at least about 1100%, at least about 1200%, at least about 1300%, at least about 1400%, at least about 1500%, at least about 1600%, at least about 1700%, at least about 1800%, or at least about 1900% greater than the C max  exhibited by a non-nanoparticulate formulation of griseofulvin, administered at the same dosage;    (c) the AUC is selected from the group consisting of at least about 25%, at least about 50%, at least about 75%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 550%, at least about 600%, at least about 750%, at least about 700%, at least about 750%, at least about 800%, at least about 850%, at least about 900%, at least about 950%, at least about 1000%, at least about 1050%, at least about 1100%, at least about 1150%, or at least about 1200% greater than the AUC exhibited by the non-nanoparticulate formulation of griseofulvin, administered at the same dosage; or    (d) a combination thereof.    
     
     
         81 .- 84 . (canceled)  
     
     
         85 . The method of  claim 60 , wherein the griseofulvin composition does not produce significantly different absorption levels when administered under fed as compared to fasting conditions.  
     
     
         86 . The method of  claim 85 , wherein the difference in absorption of the griseofulvin composition of the invention, when administered in the fed versus the fasted state, is selected from the group consisting of less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, and less than about 3%.  
     
     
         87 . The method of  claim 60 , wherein administration of the composition to a human in a fasted state is bioequivalent to administration of the composition to a human in a fed state.  
     
     
         88 . The method of  claim 87 , wherein “bioequivalency” is established by: 
 (a) a 90% Confidence Interval of between 0.80 and 1.25 for both C max  and AUC;    (b) a 90% Confidence Interval of between 0.80 and 1.25 for AUC and a 90% Confidence Interval of between 0.70 to 1.43 for C max ; or    (c) a combination thereof.    
     
     
         89 . (canceled)  
     
     
         90 . The method of  claim 60 , wherein the subject is a human.  
     
     
         91 . The method of  claim 60 , used to treat a condition selected from the group consisting of: 
 (a) dermatophyte infections and ringworm infections;    (b) ringworm infections of the scalp, hair, nails, and skin;    (c)  Tinea capitis  (ringworm of the scalp),  Tinea corporis  (ringworm of the body),  Tinea pedis  (athlete's foot),  Tinea unguium  (ringworm of the nails),  Tinea cruris  (ringworm of the thigh), and  Tinea barbae  (barber's itch);    (d) a fungal infection of an organism selected from the group consisting of  Trichophyton rubrum, Trichophyton tonsurans, Trichophyton mentagrophytes, Trichophyton interdigitalis, Trichophyton verrucosum, Trichophyton sulphureum, Trichophyton schoenleini, Trichophyton audouini, Trichophyton canis, Trichophyton gypseum, Trichophyton floccosum, Trichophyton megnini, Trichophyton gallinae,  and  Trichophyton crateriform;  or    (e) a combination thereof.    
     
     
         92 .- 94 . (canceled)